Targeted therapies show promise improving outcomes across several hematologic malignancies

IMAGE: Four studies being presented today at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta highlight the multiple ways in which novel targeted cancer therapies are...
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Credit: American Society of Hematology

(Atlanta, December 10, 2017) -- Four studies being presented today at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta highlight the multiple ways in which novel targeted cancer therapies are now being deployed to improve outcomes and quality of life for patients with rare, advanced, or difficult-to-treat blood malignancies.

Most standard chemotherapy drugs work by killing cells in the body that are growing and dividing rapidly; this includes cancer cells, but the drugs don't distinguish between cancer cells and normal cells. Targeted drugs, by contrast, are designed to zero in on and neutralize genetic features of cancer cells that make them different from normal cells and allow the cancer cells to grow and spread. Because they are designed to specifically target cancer cells while leaving normal cells alone, targeted therapies usually have different, and sometimes milder, adverse side effects than standard chemotherapy drugs.

"These studies illustrate how better scientific understanding of what drives cancer at the molecular level is leading to novel therapies capable of keeping patients' cancers in check for extended periods of time, while also helping them achieve better quality of life," said press briefing moderator Laurie Sehn, MD, medical oncologist at the British Columbia Cancer Agency and clinical professor at the University of British Columbia in Vancouver, Canada.

This press conference will take place on Sunday, December 10, at 8:00 a.m. EST in Room A315 of the Georgia World Congress Center.

In a large, international, randomized Phase III trial, patients with previously treated cutaneous T-cell lymphoma (CTCL) who received the investigational targeted drug mogamulizumab had significantly better progression-free survival, response rate, and quality of life than patients who received vorinostat, a U.S. Food and Drug Administration (FDA)-approved standard-of-care treatment for patients with CTCL. The adverse events observed with mogamulizumab treatment were generally mild to moderate in severity.

The primary endpoint was progression-free survival -- the time elapsed until the cancer began to show signs of getting worse -- or death for any reason. Among 372 patients included in the trial, the median progression-free survival was 7.7 months for patients treated with mogamulizumab, compared with 3.1 months for those treated with vorinostat, reported lead study author Youn H. Kim, MD, professor of dermatology and director of the Multidisciplinary Cutaneous Lymphoma Program at the Stanford University School of Medicine.

"We found that mogamulizumab has convincing clinical activity, not just in skin, but also in clearing malignant T-cells in the blood and lymph nodes," said Dr. Kim. "Progression-free survival and overall global response outcomes are clearly superior, the side effects are tolerable, and we see measurable improvements in quality of life with mogamulizumab compared with vorinostat. Taken together, these findings represent a durable and clinically meaningful benefit for patients with CTCL."

CTCL is a rare cancer of the white blood cells, specifically T lymphocytes, that primarily occurs in the skin. It is caused when T cells (cells in the immune system that help the body fight infection) begin to grow uncontrollably and build up in the skin. CTCL can also involve the blood, lymph nodes, and internal organs.

Mogamulizumab targets a protein (CCR4) that is frequently found on the surface of cancer cells in patients with CTCL. As a CCR4 antibody, the drug exploits the patient's immune cells to attack the cancer, Dr. Kim explained. Vorinostat, one of several drugs approved by the FDA to treat CTCL, works by blocking the action of an enzyme that helps cancerous T-cells survive and multiply.

Adverse effects such as diarrhea, nausea, altered taste, decreased appetite, increased blood creatinine levels, and decreased platelet counts occurred more than twice as frequently in patients treated with vorinostat than in those treated with mogamulizumab, said Kim. By contrast, the adverse effects seen most frequently in patients treated with mogamulizumab were drug rash and infusion-related reactions, such as chills and flushing. Mogamulizumab was administered as a once-weekly intravenous infusion for the first 28-day cycle and every two weeks during subsequent cycles. Vorinostat was taken as a once-daily pill.

Dr. Kim says the next step will be to learn more about biomarkers that can predict treatment outcome, and to test whether clinical benefit can be further improved by combining mogamulizumab with skin-directed or other systemic therapies that have different mechanisms of action.

Funding for this study was provided by Kyowa Kirin Pharmaceutical Development.

Youn H. Kim, MD, of Stanford University, will present this study during an oral presentation on Monday, December 11, at 4:30 p.m. EST in the Marcus Auditorium of the Georgia World Congress Center.

Patients with advanced Hodgkin lymphoma (HL) who were treated with a multi-drug regimen that included the targeted agent brentuximab vedotin (BV) had a 23-percent reduction in the risk of disease progression, death, or the need for additional therapy, compared with patients who received the standard four-drug first-line regimen for treating advanced HL, researchers reported.

In this multinational, Phase III clinical trial, the addition of BV to standard treatment improved patients' chances of being cured with the first round of treatment, avoiding the need for additional, more intensive therapy. The study results represent the first successful effort in more than 30 years to improve outcomes of first-line treatment in patients with advanced HL without escalating the toxicity of the chemotherapy to unacceptable levels, said lead study author Joseph M. Connors, MD, clinical director of the British Columbia Cancer Agency Centre for Lymphoid Cancer in Vancouver, Canada.

Standard treatment for HL, consisting of the drugs Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine (ABVD), has not changed since the 1970s, said Dr. Connors, adding that previous trials have failed to improve the outcomes achieved with ABVD without causing severe side effects.

"We expect ABVD to cure about three-quarters of patients -- which means, of course, that one quarter will not be cured," he explained. "In this study we've been able to significantly reduce that rate of treatment failure. If this new regimen is widely adopted, it will change first-line treatment of advanced HL."

BV works by first attaching to the surface of HL cells, then entering the cells to deliver a toxic substance, he said. This is the first time a drug designed to take advantage of a specific biologic characteristic of HL cells has been used in first-line treatment of the disease, he said.

HL originates in white blood cells and commonly occurs in young people. An estimated 8,200 cases will be diagnosed in the United States in 2017. The average age at diagnosis is 39. In about two-thirds of patients, the disease has spread widely throughout the body at diagnosis. If first-line therapy fails, patients must undergo a second round of more intensive treatment.

In the study, 1,334 patients with previously untreated advanced HL were randomly assigned to receive either ABVD or BV plus doxorubicin, vinblastine, and dacarbazine (AVD), with up to 50 months' follow-up. Treatment was deemed to have failed if patients' lymphoma did not completely disappear or if its persistence prompted additional non-study treatment. Although the experimental combination of BV and AVD caused more nerve damage, episodes of fever, and neutropenia (low levels of infection-fighting white blood cells) than ABVD, the nerve damage largely reversed during follow-up and the rate of serious infections could be kept to low levels with the use of medication to encourage infection-fighting white blood cells to recover more quickly, according to Dr. Connors. The experimental combination of BV and AVD meant patients didn't receive bleomycin, which has been linked to lung damage and sometimes death.

"The experimental combination with BV more frequently got rid of all of the disease, and this was achieved with acceptable levels of adverse effects," said Dr. Connors. "Treatment with BV was modestly more toxic, but when we added simple measures to improve patients' blood counts, they were able to take it safely."

Funding for this study was provided by Seattle Genetics and Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Joseph M. Connors, MD, of the British Columbia Cancer Agency Center for Lymphoid Cancers, will present this study during the plenary session on Sunday, December 10, at 2:00 p.m. EST in Hall C2 of the Georgia World Congress Center.

One-third of patients with previously treated chronic lymphocytic leukemia (CLL) had no detectable disease after six months of combination therapy with the targeted agents ibrutinib and venetoclax, with no increase in the occurrence of tumor lysis syndrome (TLS), a serious treatment side effect, researchers from the United Kingdom reported.

Of 36 patients who completed six months of combination treatment, all responded and 33 percent achieved the deepest measurable level of remission, with no detectable disease in the bone marrow, said lead study author Peter Hillmen, MBChB, PhD, professor of experimental hematology at Leeds Institute of Cancer and Pathology in the UK.

"These initial results are particularly impressive in a patient population for whom previous therapies have failed," he said. "We have shown that the two drugs can be given in combination without obvious additional toxicity, and the inability to detect disease with the most sensitive tools we have is a very good sign that the combination is proving to be an effective treatment."

Ibrutinib works by blocking signals that stimulate cancerous cells to multiply, whereas venetoclax promotes tumor cell death by blocking a protein that helps the cells survive. Both medications are approved by the FDA as single-agent therapies to treat CLL. Because the mechanisms of action of the two drugs are complementary, Dr. Hillmen and his colleagues wanted to evaluate them as combination therapy.

The Phase III CLARITY trial enrolled a total of 50 patients with CLL that had relapsed or had not responded to prior treatment. Patients' median age was 64 years. After eight weeks of treatment with ibrutinib alone, venetoclax was added at a low dose that increased over several weeks. Before starting venetoclax, patients also began taking a drug to prevent tumor lysis syndrome (TLS), organ damage caused by a buildup in the bloodstream of uric acid and other waste products of cancer cell death. To date, only one patient in the CLARITY trial has developed TLS and was safely treated without adverse effects.

"We have not seen an increase in the rate of TLS with the combination regimen compared with what we would expect to see with venetoclax single-agent therapy," Dr. Hillmen said.

After six months of combination therapy, the trial has already exceeded the expected proportion of patients achieving undetectable CLL, Dr. Hillmen added.

"Our assumption was that the trial would be a success if 30 percent of patients achieved the deepest level of remission after 12 months of combination therapy," he said. "But already, at six months, 33 percent of patients have undetectable disease."

Results for the trial's secondary endpoints of safety and absence of detectable disease in the bone marrow after six and 24 months of combination therapy will be reported at a later time, Dr. Hillmen said.

A key limitation of the study is that it lacked a control group. On the basis of the CLARITY results, Dr. Hillmen is leading a randomized controlled Phase III trial, the FLAIR trial, to compare the ibrutinib plus venetoclax combination with both ibrutinib alone and a combined regimen of three chemotherapy drugs in patients with previously untreated CLL.

Funding for this study was provided by Bloodwise, a UK-based blood cancer charity; Pharmacyclics, the manufacturer of ibrutinib; and AbbVie, the manufacturer of venetoclax.

Peter Hillmen, MBChB, PhD, of the Leeds Institute of Cancer and Pathology, will present this study during an oral presentation on Sunday, December 10, at 12:00 p.m. EST in Building B, Level 5, Murphy BR 3-4 of the Georgia World Congress Center.

Rapid Responses, Few Adverse Effects Seen with Targeted Agent in Phase I Trial in Rare Blood DisorderClinical Activity in a Phase 1 Study of BLU-285, a Potent, Highly-Selective Inhibitor of KIT D816V in Advanced Systemic Mastocytosis[2]

In a Phase I trial, patients with an advanced or aggressive form of systemic mastocytosis (AdvSM), a rare blood disorder, had rapid and durable responses with few adverse effects following treatment with an investigational drug that targets the genetic mutation found in more than 90 percent of cases.

The once-daily pill, BLU-285, targets a mutation called KIT D816V that is found in almost all cases of AdvSM, a disease that originates in mast cells, a type of white blood cell.

"We are seeing a high rate of rapid and durable responses, with a very low rate of adverse side effects, in patients with an advanced or aggressive form of the disease," said lead study author Daniel J. DeAngelo, MD, PhD, an associate professor of medicine at Harvard Medical School and a member of the adult leukemia program at the Dana-Farber Cancer Institute in Boston. "The rapidity of the improvement is extremely dramatic."

In the study, BLU-285 quickly produced lasting reductions in both cellular levels of mast cells and molecular levels of the mutated gene. Of 18 evaluable patients with aggressive systemic mastocytosis, 72 percent had an overall response, and 100 percent had disease control.

The normal role of mast cells is to help protect the body from infection and aid in wound healing. Systemic mastocytosis occurs when mast cells start to grow uncontrollably. In its aggressive form, it spreads rapidly throughout the body, invading the liver, spleen, and organs of the gastrointestinal tract. It can also develop into a rare blood cancer, mast cell leukemia. Existing treatments for AdvSM are of limited effectiveness.

BLU-285 was designed specifically to block the genetic mutation that drives the growth and spread of mast cells in AdvSM, Dr. DeAngelo said.

The primary objective of the Phase I study was to identify the "maximum tolerated dose" of BLU-285 -- that is, the highest dose that could be given without unacceptable levels of adverse effects. Secondary objectives were to assess the drug's activity in the body, including anti-cancer activity.

In the BLU-285 dose escalation study, the first three patients enrolled receive a low dose of the study drug and were monitored for adverse effects. If no adverse events were seen, the next three patients receive a higher dose, and so on. Dose escalation was stopped when adverse events were seen in 30 percent of the patients treated. Dosing began at 30 mg per day and increased in a stepwise fashion to 400 mg per day.

This Phase I trial was designed primarily to identify a safe dose of BLU-285, not to evaluate the drug's effectiveness. The investigators are now planning a Phase II study that will assess the effectiveness of a once-daily dose of 300 mg of BLU-285 in a larger number of patients.

Funding for this study was provided by Blueprint Medicines, which manufactures BLU-285.

Daniel J. DeAngelo, MD, of the Dana Farber Cancer Institute, will present this study during the plenary session on Sunday, December 10, at 2:00 p.m. EST in Hall C2 of the Georgia World Congress Center.

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The study authors and press program moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting. For the complete annual meeting program and abstracts, visit http://www.hematology.org/annual-meeting. Follow @ASH_hematology and #ASH17 on Twitter and like ASH on Facebook for the most up-to-date information about the 2017 ASH Annual Meeting.

The American Society of Hematology (ASH) is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 50 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The Society publishes Blood®, the most cited peer-reviewed publication in the field, as well as the online, open-access journal, Blood Advances®.

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